Current approaches for the treatment of primary malignant glioma (GBM) are largely unsuccessful, with most GBM recurring at or adjacent to their site of origin, indicating a failure to eradicate local tumor growth; moreover, these treatments lack tumor specificity, frequently inducing normal brain toxicity, resulting in decline in quality of life. Our hypothesis is that these limitations can be overcome by combining a GBM reactive monoclonal antibody (MAb) with a radionuclide emitting highly cytotoxic and focal radiation. Our clinical goal is to evaluate the therapeutic potential of 211At-labeled anti-tenascin MAb 81C6 in newly diagnosed GBM patients. Astatine-211 emits ?-particles that have a greater cytotoxic effectiveness and are less susceptible to resistance than conventional radiation, and have a range in tissue of only a few cell diameters, characteristics that can offer important advantages for brain tumor treatment. In our pilot study performed with chimeric 81C6 (ch81C6) labeled via N-succinimidyl 3-[211At]astatobenzoate (SAB) in recurrent brain tumor patients, encouraging responses were obtained with minimal toxicity, with 2 GBM patients surviving for nearly 3 years. However, the maximum tolerated dose was not determined because of radiolysis-induced problems with 211At labeling at higher activity levels. Basic radiochemistry investigations over the past few years have now yielded a solution to this problem. In parallel, our preclinical goal is to lay the groundwork for eventual clinical evaluation of 211At-labeled ch81C6 combined with MAb labeled with a low-energy ?-emitter to extend the zone of therapeutic effectiveness beyond the SCRC interface.
Our Specific Aims are: 1) To complete radiochemistry studies optimizing labeling of ch81C6 with 211At at the activity levels needed for reliable dose escalation;2) to conduct a Phase I/II clinical trial of 211At-labeled ch81C6 administered into the SCRC of newly diagnosed GBM patients, with the Phase 1 study done at escalating doses of 211At (mCi) and the Phase II dose at a targeted radiation dose (Gy) to the SCRC margins;3) to evaluate efficacy and normal tissue toxicity of an anti-tenascin 81C6 combination therapy approach utilizing the ?-particle emitter 211At and either the ?-particle emitter 177Lu or 131I.
Glioblastoma (GBM), the most common and malignant primary brain tumor, is uniformly lethal. Current approaches to GBM treatment are not effective, with nearly all GBM recurring, and in the very few who are long-term survivors, non-specific toxicity to normal brain compromises quality of life. Herein, we seek to specifically target highly cytotoxic radionuclides to GBM with monoclonal antibodies to treat this disease without the debilitating side effects associated with current therapeutic approaches.
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